The ability to rapidly and specifically regulate the activity of selected proteins and macromolecular complexes is essential to parse out critical functions in complicated macromolecular systems (e.g., signal transduction, protein trafficking, cell division). See e.g., J. E. Rothman, Mol Biol Cell 2010, 21, 3776; C. Brieke, et al., 2012, Angew Chem Int Ed Engl 2012, 51:8446. In combination with functional assays such as imaging, immunoprecipitation, western blot analysis, RT-PCR, and the like, perturbing the function of specific proteins of interest can reveal novel associations, critical post-translation modifications, and up-stream and down-stream effectors. Although small molecule inhibitors exist that lend themselves to such analyses (e.g., protein kinase, histone deacetylase, protease, and G protein-coupled receptor inhibitors), the actions of most of these inhibitors are primarily focused on a small subset of enzymes that are frequently therapeutic targets. In fact, only 2% of all predicted human gene products (mostly kinases) have been successfully targeted with small molecules, and it is estimated that only 10-15% of the human genome is ‘druggable.’ See e.g., S. J. Dixon & B. R. Stockwell, 2009, Curr Opin Chem Biol 13:549. Thus, there is a tremendous gap in that only a handful of gene products can be studied using small molecule inhibitors, while there is a paucity of useful inhibitors for the remaining 85-90% of gene products.
The limited number of novel small molecule inhibitors stems from multiple sources and is partially because a large number of gene products act as components of macromolecular complexes and bind to their respective target(s) through extended surface contacts. The binding affinity and specificity for these interactions arise through multiple weak interactions, and the protein targets frequently lack a deep, solvent occluded cleft as is typically found in enzymes. See e.g., K. Sugase, et al., 2007, Nature 447, 1021; V. N. Uversky, et al., 2005, J Mol Recognit 18:343. Moreover, many proteins share common domains, and thus potential inhibitors may target a common domain and therefore could lack the required specificity and produce off-target effects.
Provided herein are compositions and methods addressing these and other needs in the art.